Imatinib of formula I, functions as specific inhibitor of a number of tyrosine kinase enzymes and is chemically known as N-{5-[4-(4-methyl-piperazinomethyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine.

It is indicated for the treatment of chronic myeloid leukemia (CML), Philadelphia chromosome positive leukemia, for patients in chronic phase and in blast crisis, accelerated phase and also for malignant gastrointestinal stromal tumors. It selectively inhibits activation of target proteins involved in cellular proliferation. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. Imatinib is sold in U.S. by Novartis as Gleevec tablet containing imatinib mesylate equivalent to 100 or 400 mg of imatinib free base.
Imatinib and other related compounds were first disclosed in U.S. Pat. No. 5,521,184, wherein imatinib is prepared by involving amine intermediate of formula II, as shown below in scheme:

Imatinib is prepared by stirring a solution of amine intermediate of formula II with 1.14 meq (mol equivalent) of 4-(4-methylpiperazino methyl)benzoyl chloride in pyridine at room temperature for 23 hours to give crude product which is further slurried in dichloromethane/methanol and separated by column chromatography.
In our hands, we have found that crude product prepared by the above process; contain approximately 17 to 18% amine intermediate of formula II as an impurity which on chromatographic separation reduced to 0.08% (800 ppm). Use of column chromatography makes the process not suitable to employ for industrial synthesis being time consuming and tedious process. Even after performing tedious and time consuming chromatographic separation, amine intermediate of formula II which bears structural alerts, and is positive in several genotoxicity system still remain in the product up to 800 ppm as an impurity, which is unacceptable from regulatory requirements for genotoxic impurities.
Presence of amine intermediate of formula II as an impurity in the final product i.e. imatinib mesylate also yielded toxicological findings (hyperplasia, necrosis) in various organs in a 4-week study in rats. Such genotoxic compounds are believed to have potential to exert non-reversible changes in genetic material.
According to regulatory authorities, such as FDA, EU authorities, and in guidelines issued by ICH (The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), a drug manufacturer must submit data demonstrating that the product intended for marketing complies with regulations with regard to the content of impurities. The content of an unidentified impurity cannot exceed 0.1% (1000 ppm) by weight, while the amount of a known impurity cannot exceed 0.15% (1500 ppm). The drug manufacturer usually submits analytical data to the regulatory authority demonstrating that content of each impurity is in accordance with regulations. The regulatory authority checks the submitted data in order to ensure that the drug is having acceptable amount of impurities and is suitable for marketing. But this level of 0.1% (1000 ppm) or 0.15% (1500 ppm) may be even unacceptably high for an impurity if it is genotoxic.
According to a study carried out by Novartis, limit for this amine intermediate of formula II as an impurity in the final product can be 20 ppm based on technical feasibility. Further analysis results carried out on Gleevec tablet for quantification of amine intermediate shows its presence as 2-3 ppm.
The control of impurities bearing a genotoxic potential in pharmaceutical products has received more and more attention over the past years. As genotoxic impurities are considered to be harmful for the patient administrating the drug like imatinib mesylate, so these should be controlled at minimum possible level. Therefore synthetic process should be capable of producing imatinib mesylate with low amount of amine intermediate of formula II as an impurity.
There are several known processes reported for the preparation of imatinib and its mesylate salt but are either silent about the level of amine intermediate as an impurity in imatinib or yields the product with unacceptable amount of impurity.
U.S. Pat. No. 7,507,821 discloses preparation of imatinib by stirring a mixture of amine intermediate of formula II with 1.23 mole equivalent of 4-(4-methylpiperazino methyl)benzoyl chloride in pyridine at 50° C. for 4.5 hours to give imatinib which is slurried one or more times in ethyl acetate to yield imatinib of 97% purity. Use of pyridine makes the process disadvantageous as it is difficult to remove residual traces from final product.
U.S. Pat. No. 7,550,591 discloses a process for preparation of imatinib by stirring amine intermediate of formula II and 1.11 mole equivalent (meq) of 4-(4-methylpiperazino methyl)benzoic acid in tetrahydrofuran and water for 20 minutes followed by addition of 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride and then further stirring for one hour to give imatinib which is then purified to give product having amine intermediate 0.01% (100 ppm). Presence of unacceptable amount of the genotoxic impurity i.e. amine intermediate of formula II makes the process not amenable for regulatory market.
U.S. Pat. No. 7,638,627 discloses a process for preparation of imatinib by suspending amine intermediate of formula II in dimethylformamide followed by addition of 1.28 meq of 4-(4-methylpiperazino methyl)benzoyl chloride dihydrochloride and heating at 70° C. for 15 hours to give imatinib trihydrochloride monohydrate followed by basification with aqueous ammonia to give imatinib. Process involves an extra step of generation of trihydrochloride salt and then its neutralization to give imatinib free base.
US patent application 2008/0103305 discloses preparation of imatinib by adding 1.1 meq of 4-(4-methylpiperazino methyl)benzoyl chloride dihydrochloride to a solution of amine intermediate of formula II in pyridine followed by stirring at 15-20° C. for 1 hour and heating to 40° C. to give imatinib of purity more than 98%. Use of pyridine makes the process disadvantageous as it is difficult to remove residual traces from final product and process silent about the presence or absence of genotoxic impurity.
PCT publication WO 2008/24829 discloses preparation of imatinib by condensation of amine intermediate of formula II with 1.11 mole equivalent of 4-(4-methylpiperazino methyl)benzoyl chloride dihydrochloride in the presence of anhydrous pyridine at 20° C. for 18 hours to give imatinib which was further purified with silica gel chromatography.
PCT publication WO 2008/0117298 discloses preparation of imatinib by the reaction of amine intermediate of formula II with 1.22 meq of 4-(4-methylpiperazino methyl)benzoyl chloride dihydrochloride in the presence of base to form imatinib which is then washed with isopropanol, suspended in water followed by extraction with chloroform, distillation and treatment of residue with ethyl acetate give imatinib.
PCT publication WO 2008/136010 discloses a process for the preparation of imatinib by reaction of amine intermediate of formula II with 0.57 meq of 4-(4-methylpiperazino methyl)benzoyl chloride in chloroform and potassium hydroxide at 25-35° C. for 4 hours to give imatinib.
Most of the prior art processes are silent about amount of genotoxic impurity i.e. amine intermediate of formula II in final product. It is observed that when amine intermediate of formula II is reacted with 4-(4-methylpiperazino methyl)benzoic acid or reactive derivatives or their salts with molar ratio of amine intermediate to benzoic acid or its derivative in the range of 1:1 to 1:1.30, it finally results in imatinib mesylate having genotoxic amine intermediate of formula II more than 100 ppm, which is not acceptable.
In addition to concern of genotoxic impurity, prior art processes for the synthesis of α-form of imatinib mesylate does not produce reproducible results.
U.S. Pat. No. 6,894,051 ('051) discloses preparation of imatinib mesylate in two crystalline forms such as α-crystal form and β-crystal form. U.S. '051 patent describes α-crystal form of imatinib mesylate characterized by needle shaped crystals and hygroscopic nature, which make it unsuitable for pharmaceutical formulation as solid dosage forms. Patent discloses a process for preparing the α-crystal form wherein imatinib base was suspended in ethanol; methane sulfonic acid was added and heated under reflux for 20 minutes and than filtered at 65° C. The filtrate was evaporated down to 50% and the residue filtered off at 25° C. The mother liquor was evaporated to dryness. Both residues were suspended in ethanol and dissolved under reflux with addition, of water, cooling overnight to 25° C., filtration and drying yielded imatinib mesylate α form. The above mentioned process does not give reproducible results due to its cumbersome nature and always results in mixture of forms α and β form.
Various other references like U.S. Pat. No. 7,732,601, US patent application nos. 2006/0223816, 2007/0265288, 2008/0255138, 2008/0090833; PCT publication nos. 2006/048890, 2009/151899; an Indian application no. 216/KOLNP/2009 etc. discloses process for the preparation of α-form of imatinib mesylate. It has been noticed that polymorphic α form of imatinib mesylate when prepared as per the process reported in the prior art is not isolated in pure form it is contaminated with other forms such as β form or found to have residual solvent in unacceptable amounts.
Further prior art processes are associated with one or more disadvantages such as use of pyridine, chromatographic techniques, low purity of imatinib, inconsistency in yielding α-form. In view of the above, there exists a need for an improved process for preparing imatinib mesylate which yields the product containing acceptable levels of genotoxic impurity, i.e., less than 20 ppm, as required by the regulatory authorities. There is also a need to develop an a reproducible and improved process wherein α form of imatinib mesylate is isolated consistently in pure form without contamination of other forms and have residual solvents in specified limits.
Therefore, present invention fulfill the need in the art and provides a process for preparation of imatinib or its mesylate salt that circumvent disadvantages associated with prior art, proved to be advantageous from industrial point of view and also fulfill purity criteria's led by various regulatory authorities. Present invention also provides an efficient and reproducible process for the preparation of α-form of imatinib mesylate using new solvent system.